Interferon-gamma (IFNg) has been implicated in the pathogenesis of a number of intraocular inflammatory diseases of infectious or presumed autoimmune etiology. This includes patients with uveitis, proliferative vitreoretinopathy and idiopathic inflammatory eye diseases. Biological effects of IFNg are mediated primarily at the level of gene transcription. In this study, we characterized transcription regulatory proteins whose activities underlie effects of IFNg on human retinal pigmented epithelial cells (HRPE). We found that HRPE cells constitutively express two members of the interferon regulatory factor (IRF) family of transcription factors, IRF-1 and IRF-2. After exposure to IFNg, transcription of IRF-1 and interferon consensus sequence binding protein (ICSBP) genes is induced; IRF-2 gene transcription is not up-regulated. We further show that activation of IFN-g-responsive genes is mediated by tyrosine- phosphorylation of the STAT1 transcription factor. Thus, IFNg functions in this important retinal cell are mediated by IRF- 1, ICSBP and STAT1 transcription factors, suggesting that these proteins may provide additional targets for therapeutic modulation of the biological activities of IFNg in intraocular diseases involving the retina. - RPE; IRF-1; IRF-2; ICSBP; Interferon gamma; STAT1; Interferon-inducible transcription factors